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Full text release has been delayed at the author's request until August 16, 2025

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Characterizing Germline Genomic Diversity as a Modifier of Clinical Outcomes in Individuals with Germline PTEN Variants

Kim, Adriel Yejin
http://orcid.org/0000-0002-4186-8725
http://rave.ohiolink.edu/etdc/view?acc_num=case1721702197040716

Abstract Details

2024, Doctor of Philosophy, Case Western Reserve University, Molecular Medicine.
PTEN hamartoma tumor syndrome (PHTS) is a genetic disorder affecting individuals with germline PTEN variants. The affected individuals have a wide spectrum of clinical features ranging from cancer to neurodevelopmental disorders (NDD), including autism spectrum disorder (ASD). However, factors that underlie such phenotypic variability remain elusive, making it impossible to predict clinical outcomes. Here, we investigate germline genomic diversity as a modulator for the development of NDD versus cancer in PHTS. Genotype data of 376 individuals of European ancestry with PHTS were collected. Study participants included individuals with PHTS and NDD (n=117) and no-NDD (n=259), the former including n=57 with ASD and the latter including n=175 with cancer. Homozygosity burden was measured in sets of functionally relevant genes pertinent to NDD and cancer. Conservative filtration of homozygous variants was applied to identify variants in exonic or splicing sites for pathway analysis and with deleterious effects for collapsed homozygous variants analysis. Logistic regression models were performed with 10-fold cross validation to predict NDD/ASD phenotypes. We found significant enrichment of homozygous common variants (MAF≄0.01) but not rare variants (MAF<0.01) in genes involved in inflammatory processes and NDD-associated genes with low-confidence. Notably, in the ASD subgroup, homozygous common variants were enriched in genes involved in differentiation, inflammatory processes and chromatin structure regulation, NDD-associated genes with high-confidence, and regions with pathogenic copy number variants. Pathway enrichment analysis of genes harboring qualifying homozygous variants revealed pathways germane to NDD/ASD, including neuroinflammation, axonal guidance, and synaptogenesis signaling. Collapsing analysis with stringent filtration of homozygous variants suggested candidate modifier NDD/ASD genes, including GABRA4 (p=0.029) and CX3CR1 (p=0.016). Finally, prediction models for NDD/ASD using homozygosity burdens as predictors, after adjusting for sex, were validated. These models achieved 72% accuracy and 72% area under the curve (AUC) for NDD classification and 89% accuracy and 80% AUC for ASD classification. The study provides new insight that a higher burden of homozygous common variants, implying reduced genomic diversity, in genes with biological functions pertinent to NDD/ASD exists, may modify the risk of developing NDD/ASD phenotype, and could serve as a predictive marker of NDD/ASD in patients with PHTS.
Charis Eng, MD, PhD (Advisor)
Jonathan Smith, PhD (Committee Chair)
Robyn Busch, PhD (Committee Member)
Ming Hu, PhD (Committee Member)
Daniel Blankenberg, PhD (Committee Member)
116 p.
Genetics; Health Sciences; Medicine; Molecular Biology
PTEN hamartoma tumor syndrome; genomic variants; genomic modifier; neurodevelopmental disorder; phenotype prediction

Recommended Citations

Citations

  • Kim, A. Y. (2024). Characterizing Germline Genomic Diversity as a Modifier of Clinical Outcomes in Individuals with Germline PTEN Variants [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1721702197040716

    APA Style (7th edition)

  • Kim, Adriel. Characterizing Germline Genomic Diversity as a Modifier of Clinical Outcomes in Individuals with Germline PTEN Variants. 2024. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1721702197040716.

    MLA Style (8th edition)

  • Kim, Adriel. "Characterizing Germline Genomic Diversity as a Modifier of Clinical Outcomes in Individuals with Germline PTEN Variants." Doctoral dissertation, Case Western Reserve University, 2024. http://rave.ohiolink.edu/etdc/view?acc_num=case1721702197040716

    Chicago Manual of Style (17th edition)

case1721702197040716
© 2024, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.
Release 3.2.12